Alzheimer's Disease (AD) is a neurodegenerative disease which has a hidden onset and deteriorates progressively. In clinical, AD is mainly characterized by Cognitive decline, irreversible memory impairment, orientating ability disorder, language dysfunction, and the like. Brain tissue autopsy showed a large amount of senile plaques (SPs) formed by the aggregation of amyloid-β (Aβ) peptides and many neurofibrillary tangles (NFTs) formed by the filaments of highly phosphorylated tau proteins, and the lost of neurons and synapses. The amyloid deposits mentioned in the present application include, but not limited to, senile plaques.
Senile plaques formed by the amyloid deposit, which are one of the markers of AD, are used as the gold standard in the diagnosis of AD by autopsy or biopsy clinically. Recently, methods for the detection of the amyloid deposition mainly include biopsy and histological analysis of autopsy materials. Both of these two methods have obvious defects: biopsy results in relatively big trauma and has a risk, while autopsy can only be used for post mortal diagnosis. Thus, a simple, effective, and non-aggressive method for detecting and quantifying amyloid deposits in a patient's brain will be very useful for the diagnosis and treatment of related diseases, especially AD.
As amyloid deposits in brain have many same physical properties as the normal brain tissues (e.g., density and water content), it is difficult to directly image these deposits in vivo. Attempts have previously been performed to use magnetic resonance imaging (MRI) and computed tomography (CT) for the direct (without using developing agent) imaging of amyloid deposits. However, the effects of these attempts are not satisfying or amyloid deposits can only be detected under certain advantageous conditions.
Typical fluorescent dyes, such as Congo Red (CR), Thioflavin S (ThS), and Thioflavin T (ThT), are able to highly specifically bind to amyloid deposits (senile plaques) in vitro. These ligands with high affinity can be modified and labeled with positron radioactive isotopes. As a method mostly investigated recently, positron emission tomography can be used to visibly detect the distribution and amount of senile plaques in AD patients in vivo if the labeled ligands can successfully enter into brain tissues. These PET imaging agents can improve accuracy of diagnosis, provide direct estimation for the study and treatment with anti-Aβ drugs, and thus enable the diagnosis at an early stage.
The ligands used for the detection of amyloid deposits in a living brain must be able to pass through blood-brain-barrier (BBB). Congo Red, Thioflavin S, and Thioflavin T etc. can not pass through Blood-brain-barrier for their relatively bigger molecular size and charge. Ligands having a relatively smaller molecular size (compared with Congo Red) can be used to improve brain intake and increase lipophilicity. Recently, potent ligands (most of which are obtained by modification on the basis of the structures of Congo Red, Thioflavin T, and Thioflavin S) include, e.g., [11C]PIB, [123I]IBOX (Zhuang, Kung et al. 2001. 28: 887-94), [123I]IMPY, [18F]FDDNP, [11C]SB-13, [11C]-BF-227. Among these, [18F]FDDNP, [11C]PIB, [11C]SB-13, [11C]-BF-227, and [11C]-AV-45 have been used in clinical studies in AD patients and age-matched normal elderly with PET.
In the development of new therapies for the brain diseases, blood-brain-barrier (BBB) is considered as a major obstacle for the use of drugs having a potential in the treatment of central nervous system (CNS) diseases. Generally, only lipophilic molecules of less than about 500 Dalton can pass through BBB, i.e., from blood to brain. The above-mentioned PET imaging agents are all based on small chemical molecules. For passing through BBB, these small molecules should be lipo-soluble so as to pass through BBB in a passive diffusion way. However, the increased lipophilicity is always accompanied with increased non-specific binding. Thus, there is a need for an amyloid imaging agent avoiding small chemical molecule structure and passive diffusion manner, which is meaningful.
It has been reported that, angiopep-2, which is a ligand for low density lipoprotein receptor-related protein (LRP), shows higher efficiency in passing through BBB than brain-targeted groups such as transferrin. More importantly, LRP is not only expressed in brain capillary vessels endothelial cells, but also in amyloid deposits. As known in the prior art, angiopep-2, as a targeting group, can effectively improve the passing efficiency of drugs (e.g., ANG1005 from Angiochem) into intact BBB, and good therapeutic effects can be obtained. Thus, imaging agents labeled with angiopep-2 are promising in passing through BBB via a receptor-mediated action and obtaining the targeted labeling of the amyloid deposits in brain.
Up to now, it has not been reported that angiopep-2 can be used as both a BBB crossing agent and an amyloid deposit targeting agent, or amyloid deposit imaging agents labeled with imaging groups.